Chronic wounds, such as the diabetic ulcer wounds have serious effect on people's lives, and can even lead to death. Diabetic ulcer wounds are different from normal wounds and much easier to be infected and induce oxidative stress due to the special surrounding microenvironment, which makes it necessary to prepare materials with antibacterial property and antioxidant activity simultaneously. The molybdenum disulfide‐ceria (MoS2‐CeO2) nanocomposite possesses both the photo‐thermal therapy (PTT) antibacterial capability of polyethylene glycol modified molybdenum disulfide nanosheets and the antioxidant activity of cerium dioxide nanoparticles (CeO2 NPs). By combining the inherent antibacterial activity of CeO2 NPs, the MoS2‐CeO2 nanocomposite exhibits excellent PTT antibacterial capability against both gram‐positive and gram‐negative bacteria through 808 nm laser treatment, thereby reducing the risk of wound infection. Owing to the abundant oxygen vacancies in CeO2 NPs, Ce3+ and Ce4+ can transform reversibly which endows MoS2‐CeO2 nanocomposite with remarkable antioxidant ability to clear away the excessive reactive oxygen species around the diabetic ulcer wounds and promote wound healing. The results demonstrate that MoS2‐CeO2 nanocomposite is a promising class for the clinical treatment of chronic wounds especially the diabetic ulcer wounds, and 808 nm laser can be used as a PTT antibacterial switch.

Glucagon-like peptide-1 (GLP-1) mediates antidiabetogenic effects through the GLP-1 receptor (GLP-1R), which is targeted for the treatment of type 2 diabetes. Small-molecule GLP-1R agonists have been sought due to difficulties with peptide therapeutics. Recently, 6,7-dichloro-2-methylsulfonyl-3-N-tertbutylaminoquinoxaline (compound 2) has been described as a GLP-1R allosteric modulator and agonist. Using human embryonic kidney-293 cells expressing human GLP-1Rs, we extended this work to consider the impact of compound 2 on G protein activation, Ca 2ϩ signaling and receptor internalization and particularly to compare compound 2 and GLP-1 across a range of functional assays in intact cells. GLP-1 and compound 2 activated G␣ s in cell membranes and increased cellular cAMP in intact cells, with compound 2 being a partial and almost full agonist, respectively. GLP-1 increased intracellular [Ca 2ϩ ] by release from intracellular stores, which was mimicked by compound 2, with slower kinetics. In either intact cells or membranes, the orthosteric antagonist exendin-(9-39), inhibited GLP-1 cAMP generation but increased the efficacy of compound 2. GLP-1 internalized enhanced green fluorescent protein-tagged GLP-1Rs, but the speed and magnitude evoked by compound 2 were less. Exendin-(9-39) inhibited internalization by GLP-1 and also surprisingly that by compound 2. Compound 2 displays GLP-1R agonism consistent with action at an allosteric site, although an orthosteric antagonist increased its efficacy on cAMP and blocked compound 2-mediated receptor internalization. Full assessment of the properties of compound 2 was potentially hampered by damaging effects that were particularly manifest in either longer term assays with intact cells or in acute assays with membranes.

Background and purpose:The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B of the G protein-coupled receptor superfamily and is a target for treatment of type 2 diabetes. Family B G protein-coupled receptors contain a putative N-terminal signal peptide, but its role in receptor synthesis and trafficking are unclear. Further, the signal peptide is not cleaved in at least one family member. Experimental approach: We examined receptor glycosylation and the role of the signal peptide in GLP-1R synthesis and trafficking using constructs containing epitope tags at the N-and/or C-terminus and in which the signal peptide sequence was either present or absent. Key results: The signal peptide was absolutely required for GLP-1R synthesis but could be substituted to some extent by increasing positive charge in the N-terminal region of the receptor flanking the signal peptide. The signal peptide is cleaved during synthesis and processing of the receptor. An enhanced GFP-epitope tag at the N-terminus of the receptor permitted synthesis of the receptor but blocked signal peptide cleavage and prevented trafficking to the plasma membrane. Cleavage site mutation allowed synthesis of a full-length receptor, blocked signal peptide cleavage and caused retention within the endoplasmic reticulum. Conclusions and implications:Signal peptide cleavage was not essential for receptor synthesis but was obligatory for processing and trafficking of receptors to the plasma membrane. Further, the GLP-1R is subject to N-linked glycosylation and only the mature, fully glycosylated form of the receptor is present in the plasma membrane. Inhibition of glycosylation prevents processing and cell surface expression of the GLP-1R. Doyle and Egan, 2007). Enhancing GLP-1R-mediated effects through either inhibition of the rapid breakdown of GLP-1 by dipeptidyl peptidase-IV or by direct activation of the GLP-1R is now a validated therapeutic option for the treatment of type 2 diabetes. The GLP-1R belongs to the relatively small Family B of the G-protein-coupled receptor (GPCR) superfamily. Despite being integral membrane proteins with seven transmembrane a-helices, a large proportion of GPCRs (~85%) display no evidence of a signal peptide sequence (Köchl et al., 2002). This is a sequence of approximately 20 amino acids containing a stretch of hydrophobic residues, usually in the N-terminus of the protein, which is often critical for the synthesis and processing of both secreted and integral membrane proteins. However, these signal peptide sequences are removed by signal peptidases within the endoplasmic reticulum. In GPCRs without such a sequence, the first transmembrane domain can function as a signal anchor sequence, promoting post-translational movement of the N-terminus through the translocon into the lumen of the endoplasmic reticulum during which time the nascent peptide may be subject to N-linked glycosylation. Subsequently, signal anchor sequences within the receptor transmembrane domains are thought to regulate further synthesis and...

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The brand-new RE–CND hybrids are systematically reviewed for the first time, providing recent advances, interdisciplinary opportunities and challenges for researchers.

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